Bigger Is Better; A New Therapeutic Approach For Parkinson's Disease The incidence of Parkinson's disease (PD) and other neurodegenerative disorders increases with old age although the reason(s) why is not clear. But now in an article to come out this week in the journal Science1 researchers at Harvard describe a direct link between aging and neurodegeneration as well as a potential new treatment against PD. The study shows how inhibition of SIRT2- a member of the sirtuin family, which is linked to aging - prevents the toxicity of the protein aggregates that are believed to be behind the neuronal death characteristic of PD. Interestingly, and contrarily to "classic" approaches that try to eliminate these aggregates, SIRT2 inhibition appears to work by "fusing" many small protein aggregates into larger (apparently less neuro-toxic) ones. The research by showing that aging and neurodegeneration can be linked opens the door to a total new type of therapeutic approaches not only towards PD, but also other neurodegenerative diseases linked to aberrant protein deposits in the brain and known to become worst with age. In many neurodegenerative disorders, including PD, toxic aggregates of aberrant proteins found in the brain tissue of patients are believed to be behind the neural death characteristic of these diseases. In PD, the disorder seems to result from deposition of alpha-synuclein - a protein of unknown functions - which leads to neuron death in the substantia nigra (literally the black substance), a part of the brain responsible for motor control. Neurons within the substantia nigra produce the neurotransmitter dopamine (and so are called dopaminergic neurons) that acts as messenger between this "control centre" and other neurons in the body for a correct regulation of the body movements. If the substantia nigra degenerates, like it happens in PD, dopamine is no longer correctly produced and the patient starts showing the disease characteristic symptoms, which include tremors, rigidity, slowness of movements as well as problems in balance and coordination. Nevertheless, and contrary to many other neurodegenerative diseases, PD has a number of effective treatments that by increasing dopamine levels in patients' brain can efficiently alleviate the symptoms. But there is no cure and, as disease progresses, treatments become less and less efficient and full deterioration is inevitable. Tiago Fleming Outeiro, Aleksey Kazantsev and colleagues at the Harvard Medical School, Boston, the Scripps Research Institute, CA and Purdue University, IN, USA have been investigating possible new therapies for some time and previously described a molecule, called B2, which was capable of diminish alpha-synuclein neuro-toxicity and rescued dopaminergic neurons from death. Interestingly, B2 did not eliminate alpha-synuclein inclusions but instead increased their size by fusing small ones. Unfortunately, B2 did not have drug-like characteristics to allow its use in animals but was used, nevertheless, in an attempt to find structurally similar molecules - and so with big chances of having the same function - although compatible with animals/humans use. The first step was to understand how B2 worked and it was found that it specifically inhibited the activity of a protein called SIRT2. SIRT2 is a member of the sirtuin family recently described as "the anti-aging proteins" as they seem to be capable of increase the life span of a multitude of organisms. In fact, SIRT1, one of its best-known members, is increased in the presence of anti-oxidants and during caloric restriction, both conditions known to increase longevity. SIRT2, however, seemed to have the opposite effect since its inhibition diminished the number of dead dopaminergic neurons in the presence of toxic alpha-synuclein aggregates. The next step was to find molecules structurally similar to B2, capable of reacting against SIRT2 but compatible with human use. B2 structure was ran against a database and AGK2 was found, a molecule not only compatible with animals/humans administration but that also proved ten times more potent than B2 controlling alpha-synuclein toxicity. Even more important, AGK2 was able to rescue neurons from alpha-synuclein-induced death when tested in isolated cells but also in a model of Parkinson's in fruit flies. In this model flies are genetically modified to produce alpha-synuclein in their brain leading to neuron death that was drastically reduced when the flies are fed AGK2, suggesting that this molecule could be used in "real life" against PD. Like B2, AGK2 alpha-synuclein toxicity prevention is done by merging small protein inclusions into large aggregates, which goes against current therapeutic approaches. In fact, current research is aimed at the eradication of the inclusions even if it has been, by large, unsuccessful. Outeiro and colleagues' results agree, however, with other suggestions that it is the small aggregates, capable of interact with the cellular components, that are toxic while larger ones might even protect the cell machinery in charge of eliminating aberrant proteins. The research also shows that sirtuins have a larger spectrum of roles in the cell than previously thought. The exact mechanism of how SIRT2 inhibition can protect against alpha-synuclein aggregates is not understood, but the effects are clear enough for it to be seen now as a potential new therapy, not only for PD, but also other neurodegenerative diseases. Like Tiago Outeiro a Portuguese researcher and the first author of the work says "Our results establish a connection between aging and neurodegeneration, and suggest that SIRT2 might be used as a target in other neurodegenerative disorders known to be affected by age". Outeiro and colleague's research is important also because it challenges the assumption that to treat PD and other similar disorders one has to destroy the abnormal inclusions and describes a direct link between aging and neurodegeneration, and in doing this opens the door to total new kind of therapies against these diseases. And in a world where six million people worldwide - one million in the US - suffer just from Parkinson's (including 3% of the population above 65 years) with serious health and economical consequences any new treatments and approaches are more than welcome.